Epigenetic Memory of Intestinal Epithelial Cells in Inflammatory Bowel Disease

Abstract

Background: The pathogenesis of human Inflammatory Bowel Disease (IBD) is a multifactorial process including interaction between immune, epithelial, and environmental factors. Growing evidence suggests that epithelial cell defects play major role in the pathogenesis of IBD. Epigenetic memory involves lasting, cell-type specific modifications to chromatin at multiple scales, which impacts transcriptional programs required for normal cell functions. A major gap in knowledge are the mechanisms involved in establishing and maintaining memory in cell types and diseases of the intestine. The objective of this study was to determine if intestinal epithelial cells (IECs) retain a memory of altered chromatin architectures and resultant regulation following inflammation. The hypothesis was that the IECs would show lasting altered chromatin structure landscapes (epigenetic memory) in response to inflammation. Methods: We have developed a multicellular model system of IBD using adult stem cell derived organoids from humans with IBD, from regions of the colon with and without active inflammation. We performed ATAC-seq, bulk RNA-seq and single cell RNA-seq on these organoids derived from the uninflamed and inflamed tissues of IBD patients, specifically Ulcerative Colitis (UC). Results: Regions of increased chromatin accessibility are enriched in organoids derived from areas of inflammation in UC patients compared to organoids from patient-matched, uninflamed regions. These open chromatin regions are associated with proinflammatory genes, with modest transcriptional alterations, pointing to an epigenetic inflammatory memory. Motif analysis for accessibly peaks in UC showed an enrichment of the AP-1 family of transcription factors and chromatin remodelers (SMARCA4). This data is consistent with other studies of inflammatory memory from other epithelial cell types, but we show this for the first time in IECs in the context of IBD. Conclusions: This study presents a novel line of investigation and development of model systems to examine epigenetic memory of IECs in human IBD. We expect that our studies will identify new chromatin-based mechanisms of IEC function that are impacted by inflammation. This research was funded by American Gastroenterological Association Research Scholar Award and KL2 Scholar Career Development Award (KL2 TR002379, National Center for Advancing Translational Science). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.